Biologic therapy of Melanoma and Renal Cell Cancer

描述（由申请人提供）：本K24中期研究者奖申请概述了以患者为导向的研究计划，涉及使用免疫治疗策略治疗黑色素瘤和肾细胞癌（RCCA）。 首席研究员迈克尔B。阿特金斯，医学博士，1987年参加了肿瘤学培训 他是一位在生物治疗领域有成就的临床研究者，并作为研究员和初级教师的导师在癌症相关的临床研究中有着良好的记录。 他的大部分职业生涯都致力于研究黑色素瘤和RCCA的细胞因子he为基础的疗法，是FDA批准这两种疾病的高接近IL-2疗法的主要贡献者。 他最近的努力集中在通过与其他细胞因子或化疗的组合、选择性毒性阻断剂的施用、具有更有希望的治疗概况的其他细胞因子的使用或将治疗靶向于最有可能应答的那些来增强细胞因子疗法的治疗指数。 该应用程序的第一部分，包括5个特定目标和7个临床试验，涉及这项工作的最新扩展。 目标1将使用从参与III期或IV期疾病的两项III期组间试验（由阿特金斯博士领导）的黑色素瘤患者中获得的系列血液、肿瘤和淋巴结标本，以确定对基于阿托伐他汀的治疗的敏感性和耐药性的潜在机制。 目的2将在两项针对RCCA患者的CWG试验的背景下，研究T细胞受体和DC功能障碍在介导对IL-2治疗的抵抗中发挥的作用。 Aim 3将使用来自我们先前单独使用IL-12的转化研究的策略来检查将IL-2添加到IL-12治疗中的价值。 Aim 4将测试选择性结合高亲和力IL-2受体的新型IL-2将免疫激活与毒性分离的能力。 最后，Aim 5将检查来自先前CWG IL-2试验的RCCA患者的病理学材料，当对从即将接受IL-2的患者中前瞻性获得的肿瘤组织进行基因表达分析时，以确定病理学和分子相关性或反应和抗性。 该申请的第二个组成部分涉及2个目标和3个额外的临床试验，将探索旨在克服肿瘤特异性耐受的新型免疫治疗策略。 目前正在积极研究的两种方法是DC疫苗接种：肿瘤融合细胞（Aim 6）和非清髓性异基因干细胞移植（Aim 7）。 最终目标是将这些策略之联合收割机与基于细胞因子的治疗（结合具体目标1-5中的经验教训）组合，以产生针对这两种疾病的更有效的免疫治疗方法。 这些项目为研究员或初级教员提供至少四条明确的路径，以便在临床研究和实验室导师的指导下进行以患者为导向的临床研究。 与阿特金斯博士的定期会议，多学科会议，重点临床轮换和临床研究课程将完善实习生的经验。 总之，这项工作应该确定黑色素瘤或RCCA患者成功免疫治疗的关键因素，同时为下一批临床研究人员提供出色的培训，他们将被指望扩大这一努力。

DESCRIPTION (provided by applicant): This K24 Midcareer Investigator Award application outlines of program of patient-oriented research involving the use of immunotherapy strategies for the treatment of melanoma and renal cell carcinoma (RCCA). The principal investigator, Michael B. Atkins, M.D., competed his oncology training in 1987. He is an accomplished clinical investigator in the areas of biologic therapy and has a proven track record as a mentor for fellows and junior faculty pursuing careers in cancer related clinical investigation. He has devoted much of his career to the investigation of cytokine he-based therapies for melanoma and RCCA and was a major contributor to the FDA approval of high-close IL-2 therapy for these two diseases. His more recent efforts have focused on enhancing the therapeutic index of cytokine therapy either through combinations with other cytokines or chemotherapy, administration of selective toxicity blocking agents, the use of other cytokines with more promising therapeutic profiles, or the targeting of treatment to those most likely to respond. The first part of this application, encompassing 5 Specific Aims and 7 clinical trials, deals with the latest extensions of this work. Aim 1 will use serial blood, tumor and lymph node specimens obtained from melanoma patients participating in the two Phase III Intergroup trials for Stage III or IV disease (led by Dr. Atkins) to determine the mechanisms underlying sensitivity and resistance to cytokine-based therapy. Aim 2 will examine the roles that T cell receptor and DC dysfunction play in mediating resistance to IL-2 therapy in the context of two CWG trials for patients with RCCA. Aim3 will examine the value of adding IL-2 to IL-12 therapy using strategies derived from our prior translational research studies with IL-12 alone. Aim4 will test the ability of a novel IL-2 that selectively binds the high affinity IL-2 receptor, to dissociate immune activation from toxicity. Finally, Aim5 will examine pathology material from RCCA patients on prior CWG IL-2 trials, as when is perform gene expression analysis on prospectively obtained tumor tissue from patients about to receive IL-2, in order to determine pathologic and molecular correlates or response and resistance. A second component of this application, involving 2 Aims and 3 additional clinical trials, will explore novel immunotherapy strategies aimed at overcoming tumor-specific tolerance. Two approaches that are actively being studied are vaccination with DC: tumor fusion cells (Aim 6) and non-myeloablative allogeneic stem cell transplantation (Aim 7). The ultimate goal is to combine one or both of these strategies with cytokine based treatment (incorporating the lessons learned in specific aims 1-5) to produce more effective immunotherapy approaches for these two diseases. These projects provide at least four clearly defined paths for fellows or junior faculty members to pursue patient-oriented clinical research under the guidance of clinical research and laboratory mentors. Regular meetings with Dr. Atkins, multidisciplinary conferences, focused clinical rotations, and a clinical investigation course will round out the trainee experience. Taken together, this work should determine the factors critical to the successful immunotherapy of patients with melanoma or RCCA and, at the same time, provide superb training for the next cadre of clinical investigators who will be counted on to extend this effort.